Liver Fibrosis Stage Research Articles

Artificial Intelligence and Image Analysis-Assisted Diagnosis for Fibrosis Stage of Metabolic Dysfunction-Associated Steatotic Liver Disease Using Ultrasonography: A Pilot Study

Purpose: Elastography increased the diagnostic accuracy of liver fibrosis. However, several challenges persist, including the widespread utilization of equipment, difficulties in measuring certain cases, and the influence of viscosity factors. A rough surface and a blunted hepatic margin have long been acknowledged as valuable characteristics indicative of hepatic fibrosis. The objective of this study was to conduct an image analysis and quantitative assessment of the contour of the sagittal section of the left lobe of the liver. Methods: Between February and October 2020, 486 consecutive outpatients underwent ultrasound examinations at our hospital. A total of 214 images were manually annotated by delineating the liver contour to create annotation images. U-Net was employed for liver segmentation, with the dataset divided into training (n = 128), testing (n = 42), and validation (n = 44) subsets. Additionally, 43 Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) cases with pathology data from between 2015 and 2020 were included. Segmentation was performed using the program developed in the first step. Subsequently, shape analysis was conducted using ImageJ. Results: Liver segmentation exhibited high accuracy, as indicated by Dice loss of 0.044, Intersection over Union of 0.935, and an F score of 0.966. The accuracy of the classification of the liver surface as smooth or rough via ResNet 50 was 84.6%. Image analysis showed MinFeret and Minor correlated with liver fibrosis stage (p = 0.046, 0.036, respectively). Sensitivity, specificity, and AUROC of Minor for ≥F3 were 0.571, 0.862, and 0.722, respectively, and F4 were 1, 0.600, and 0.825, respectively. Conclusion: Deep learning segmentation of the sagittal cross-sectional contour of the left lobe of the liver demonstrated commendable accuracy. The roughness of the liver surface was correctly judged by artificial intelligence. Image analysis showed the thickness of the left lobe inversely correlated with liver fibrosis stage.

Significant Within-Individual Variability in VCTE Liver Stiffness Measurements at Two Intercostal Spaces in Subjects with MASLD: Implications for Evaluating Improvement in Liver Fibrosis After Weight-Loss or Liver-Directed Therapy

Introduction: Studies have compared the group-averages of liver stiffness measures (LSMs) from multiple rib spaces by vibration-controlled transient elastography (VCTE) to stage liver fibrosis. No previous study has assessed within-individual liver stiffness variation from two rib spaces in individuals with metabolic-dysfunction associated steatotic liver disease (MASLD). Methods: We evaluated within-individual LSM variation according to body weight classification and its clinical implication. From October 2019 to March 2024, VCTE was performed on MASLD patients or those at high risk, in accordance with FibroScan guidelines. The LSMs were categorized into stages: <5 kPa (stage 0), 5–7.99 kPa (stage 1), 8–9.99 kPa (stage 2), 10–13.99 kPa (stage 3), and 14+ kPa (stage 4). Measurements with 10 values and IQR/median ≤ 0.30 were included, using SPSS V25.0 for analysis. Results: Among 1107 subjects (age 54.4 ± 13.9 years, 56.9% female), 7.7% were normal weight, 20.7% overweight, 28.9% class 1 obesity, 21.3% class 2 obesity, and 21.2% class 3 obesity. Significant within-individual variation was noted: 67% (0–2 kPa) variation, 23.4% (2.1–6 kPa), and 10% (≥6.1 kPa). Class 3 obese individuals had the maximum variation. Comparing the group-average of LSM at each ICS site showed that 95% of individuals were within one fibrosis stage. Conclusions: While LSM group-averages at different rib sites provides reliable fibrosis staging, significant within-individual variability exists especially in class 3 obesity. This should be considered when serial LSM assessments are used to assess medical therapeutic efficacy.

Assessment and integration of multiparametric MRI for liver fibrosis staging in rat non-alcoholic steatohepatitis: Evaluation of diagnostic efficiency and model interpretation

ObjectivesMulti-parametric MRI techniques, including intravoxel incoherence motion (IVIM), iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL IQ), T2* mapping and T2 mapping, were employed to develop and validate a predictive model for non-alcoholic steatohepatitis (NASH) diagnosis and liver fibrosis (LF) staging in rats. The combined model was interpreted using SHapley Additive exPlanations (SHAP) values for model understanding. Materials and methods160 healthy Sprague-Dawley (SD) rats were divided into control (n = 24) and experimental (n = 136) groups, and the 12-week and 16-week groups were injected intraperitoneally with carbon tetrachloride (CCl4) for 4 weeks, one month before the final feeding period. All rats were subjected to pathological examination to determine LF stage. Upon the study’s completion, 147 SD rats were assessed for liver fibrosis. Results84 SD rats were diagnosed with NASH and 31, 10, and 43 rats were histologically diagnosed with no fibrosis (F0), early LF (F1-F2), and late LF (F3-F4). For diagnosis of NASH and staging of liver fibrosis associated with NASH, a combined multi-parameter magnetic resonance imaging prediction model has a higher area under the ROC curve (AUC) than individual diffusion parameters, especially in advanced stages of fibrosis, with an AUC of 0.929 for the combined model. In SHAP, the free fluid(FF) value contributes most to the model for diagnosing NASH and advanced liver fibrosis, while the T2 value contributes most for diagnosing liver fibrosis and the apparent diffusion coefficient (ADC) value contributes most for diagnosing liver cirrhosis. ConclusionsThe integration of several magnetic resonance imaging methods along with SHAP value analysis provides a more comprehensive and theoretical investigation into the mechanisms and factors contributing to the progression of liver fibrosis in NASH, offering insights from various angles.

Development of fully automated models for staging liver fibrosis using non-contrast MRI and artificial intelligence: a retrospective multicenter study

Accurate staging of liver fibrosis (LF) is essential for clinical management in chronic liver disease. While non-contrast MRI (NC-MRI) yields valuable information for liver assessment, its effectiveness in predicting LF remains underexplored. This study aimed to develop and validate artificial intelligence (AI)-powered models utilizing NC-MRI for staging LF. A total of 1726 patients from Shengjing Hospital of China Medical University, registered between October 2003 and October 2022, were retrospectively collected, and divided into development (n=1208) and internal test (n=518) cohorts. An external test cohort consisting of 337 individuals from six centers, registered between June 2015 and November 2022, were also included. All participants underwent NC-MRI (T1-weighted imaging, T1WI; and T2-fat-suppressed imaging, T2FS) and liver biopsies. Two classification models (CMs), named T1 and T2FS, were trained on respective image types using 3D contextual transformer networks and evaluated on both test cohorts. Additionally, three CMs-Clinic, Image, and Fusion-were developed using clinical features, T1 and T2FS scores, and their integration via logistic regression. Classification effectiveness of CMs was assessed using the area under the receiver operating characteristic curve (AUC). A comparison was conducted between the optimal models (OMs) with highest AUC and other methods (transient elastography, five serum biomarkers, and six radiologists). Fusion models (i.e., OM) yielded the highest AUC among the CMs, achieving AUCs of 0.810 for significant fibrosis, 0.881 for advanced fibrosis, and 0.918 for cirrhosis in the internal test cohort, and 0.808, 0.868, and 0.925, respectively, in the external test cohort. The OMs demonstrated superior performance in AUC, significantly surpassing transient elastography (only for staging≥F2 and ≥ F3 grades), serum biomarkers, and three junior radiologists for staging LF. Radiologists, with the aid of the OMs, can achieve a higher AUC in LF assessment. AI-powered models utilizing NC-MRI, including T1WI and T2FS, accurately stage LF. National Natural Science Foundation of China (No. 82071885); General Program of the Liaoning Provincial Department of Education (LJKMZ20221160); Liaoning Province Science and Technology Joint Plan (2023JH2/101700127); the Leading Young Talent Program of Xingliao Yingcai in Liaoning Province (XLYC2203037).

Cytokine profiling of plasma in patients with viral hepatitis C

Chronic hepatitis C (CHC) represents a significant public health concern. In the majority of cases, the infection progresses to a chronic form, which is characterised by the development of fibrosis and cirrhosis of the liver. A plethora of cytokines and chemokines are generated as a consequence of inflammatory processes within the liver. These can exert a dual effect, both protective and damaging, particularly in relation to the death of hepatocytes and the progression of liver fibrosis. Furthermore, a number of growth factors have been identified as playing a role in the pathogenesis of CHC. The objective of the study was a comprehensive evaluation of a wide range of cytokines, chemokines and growth factors in the blood plasma of patients with CHC at varying stages of liver fibrosis. The study cohort comprised 63 patients diagnosed with CHC, who were divided into three groups according to the stage of liver fibrosis. The control group comprised healthy individuals (n = 32). Concentrations of the following cytokines were determined in plasma: Interleukins and some cytokines (IL-1α, IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IL-17-E/IL-25, IL-17F, IL-18, IL-27, IFNα, IFNγ, TNFα, TNFβ); chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROα, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine) and growth factors (EGF, FGF-2, Flt-3L, G-CSF, M-CSF, PDGF-AA, PDGF-AB/BB, TGF-α, VEGF-A) by multiplex analysis based on xMAP technology. Nonparametric statistics methods were used for statistical analysis. As a result of the study, increased concentrations of cytokines IL-12 (p40), IL-15, IL-17E/IL-25, IL-27, IFNγ, TNFα, chemokines CXCL9/MIG and CXCL-10/IP-10 and growth factors FGF-2 and M-CSF were found at all stages of liver fibrosis. Elevated concentrations of cytokines IL-1α, IL-1β, IL-2, IL-6, IL-9, IL-10, IL-17F, IFNα, TNFβ, chemokines CCL2/MCP-1, CCL11/Eotaxin, CCL22/MDC and growth factors G-CSF, TGF-α, Flt-3L were found in severe liver fibrosis/cirrhosis. Correlation analysis revealed a relationship of high significance between the severity of liver fibrosis and the content of cytokines IL-6, IFNγ, TNFα, IL-7, chemokines CCL2/MCP-1, CCL11/Eotaxin, CXCL9/MIG, CXCL10/IP-10, CXCL1/GROα, growth factors TGF-α, PDGF-AA, PDGF-AB/BB. Thus, a certain profile of cytokines characteristic for CHC was revealed, cytokines, chemokines and growth factors significant for liver fibrosis in CHC were found.

Relationship between fibrosis-4 index and new onset hypertension in the general population

Abstract Background/Introduction Non-alcoholic fatty liver disease (NAFLD) is a risk for cardiovascular events and malignant tumors as well as liver cirrhosis, and the risk increases with increasing fibrosis of the liver. Thus, the fibrosis-4 (FIB-4) index, developed as a noninvasive test to stage liver fibrosis, may predict the development of hypertension. Purpose The present study investigated the relationship of FIB-4 index with the prevalence and future development of hypertension in the general population. Methods A total of 16125 participants who visited our hospital for a physical check-up at least twice from 2008 to 2018 (male=9700, 52.0±12.3 year-old) were subjected for cross-sectional analysis. Among them, 3995 participants were hypertensive. The remaining 12111 normotensive participants (male=6984, 49.5±11.9 year-old) were followed up for the median of 1643 days with the endpoint being the development of hypertension, defined as systolic blood pressure ≥140mmHg, diastolic blood pressure ≥90mmHg or the use of antihypertensive medication. FIB-4 index was calculated as follows; (age×AST)/(platelet number×√ALT). Results Cross-sectional analysis revealed that FIB-4 index was higher in hypertensive than normotensive participants (1.40±0.74 vs. 1.09±0.54, p<0.001). During the follow-up, 2819 participants (45.7 per 1000 person-year) developed hypertension. The incidence was more frequent in male (55.6 per 1000 person-year) than female participants (32.7 per 1000 person-year, p<0.001). High level of FIB-4 index (≥2.67, n=194) showed a significant impact on the incident hypertension (80.5 per 1000 person-year) as compare with middle (≥1.30, <2.67, n=3082) or low level (<1.30, n=8835) of FIB-4 index (65.4 and 38.8 per 1000 person-year, respectively). Non-adjusted hazard ratio (HR) (95% confidence interval [CI]) of FIB-4 index for the new onset of hypertension was 1.483 (1.416-1.553). In multivariate Cox hazard analysis adjusted for sex, body mass index, systolic blood pressure, pulse rate, serum creatinine, uric acid, HbA1c, LDL-cholesterol, triglyceride, hemoglobin, current smoking, frequent alcohol consumption and family history of hypertension, FIB-4 index was an independent predictor of the development of hypertension (HR 1.321, 95%CI [1.213-1.438]). Similar results were obtained in analyses of male (HR 1.382, 95%CI [1.300-1.470]) and female subgroups (HR 1.369, 95%CI [1.230-1.524]). History of viral hepatitis or frequent alcohol consumption did not affect the results (data not shown). Conclusions FIB-4 index is a useful predictor of the development of hypertension in the general population. Increased risk of cardiovascular events in patients with NAFLD may partially be attributable to the development of or coexistence with hypertension.

Diagnostic role of the fibrosis-4 index and nonalcoholic fatty liver disease fibrosis score as a noninvasive tool for liver fibrosis scoring.

Nonalcoholic fatty liver disease (NAFLD) is characterized by liver fibrosis, which serves as a crucial indicator of its progression and prognosis. Owing to the limitations of biopsy, which is the gold standard for measuring liver fibrosis, a reliable and noninvasive marker is required. We evaluated the diagnostic role of the fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with NAFLD with varying severities of liver fibrosis. The FIB-4 index and NFS were calculated using laboratory data from 121 patients who underwent liver biopsies between January 2022 and December 2023. The results were compared with those of the Scheuer scoring system for liver biopsies (F0, F1 + F2, and F3 + F4) to determine the sensitivity and specificity of the FIB-4 index and the liver disease fibrosis score in detecting and staging liver fibrosis. Twenty-one patients had advanced fibrosis (F3-F4), and 100 had minimal or mild fibrosis (F0-F2). The degree of liver fibrosis increased with decreased albumin, alanine aminotransferase and platelet count levels, and increasing age. Receiver operating characteristic curve analysis for the FIB-4 index and NFS revealed that the areas under the curve for the FIB-4 index and NFS were 0.895 (95% confidence interval: 0.836-0.954) and 0.882 (95% confidence interval: 0.813-0.952), respectively. The FIB-4 indices showed 95.24% sensitivity at a cutoff point of 1.30, and 85% specificity at a cutoff point of 2.67, while the NFS indices showed 95.24% sensitivity at -1.455 cutoff point and 95% specificity at a cutoff point of 0.676. The FIB-4 index and NFS may replace biopsy for the detection of fibrosis in patients with NAFLD.

Hepatic Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Levels Decline in Hepatitis C but Are Not Associated with Progression of Hepatocellular Carcinoma.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

A multi-institutional study on Ultrasound image analysis for staging HBV-derived liver fibrosis: a potential non-invasive alternative to liver stiffness measurement

Background: Liver stiffness measurement is principal for staging liver fibrosis but not included in routine examinations. We investigated whether comparable diagnostic performance can be achieved by mining ultrasound images and developing a novel serum index (NSI). Methods: Texture features were extracted from ultrasound images. Spearman correlation and logistics regression selected independent variables for significant (F≥2) and advanced (F≥3) fibrosis. We compared the diagnostic performance of transient elastography (TE), ultrasound image biomarker (UIB), conventional serum indices (APRI, FIB-4, GPR), and NSI in 365 chronic hepatitis B patients. Results: Among patients, 52.1% had significant fibrosis and 24.2% had advanced fibrosis. PLT, GGT, prealbumin, and globulin were incorporated into NSI. In the validation group, TE achieved the best performance (AUC: 0.765 [0.690-0.849] for significant fibrosis; 0.812 [0.745-0.878] for advanced fibrosis), followed by UIB (AUC: 0.712 [0.629-0.795]; 0.678 [0.595-0.763]) and NSI (AUC: 0.630 [0.534-0.725]; 0.659 [0.572-0.745]), outperforming conventional indices. Conclusions: Texture analysis enhances ultrasound's diagnostic utility, but TE remains superior. When TE is unavailable, ultrasound image analysis and NSI, incorporating prealbumin, can serve as alternative tools for fibrosis staging.

Recent advances of nanomaterials in imaging liver fibrosis

AbstractLiver fibrosis is a pathological process resulting from prolonged exposure to various injury factors. It is characterized by the abnormal proliferation and activation of hepatic stellate cells and excessive deposition of extracellular matrix. If left untreated, it can progress to cirrhosis, liver failure, and even liver cancer. There is currently no efficient and accurate clinical diagnostic method for early liver fibrosis. Therefore, there is an urgent need to address the challenge of accurate staging and early diagnosis of liver fibrosis in clinical practice. Recently, nanomaterials have demonstrated significant potential for enhancing the diagnosis of liver fibrosis. Nanomaterials possess the ability to precisely identify and target the microenvironment associated with liver fibrosis. By enhancing their enrichment in the target area, nanomaterials can improve imaging contrast of fibrosis lesions in the liver, thereby enabling accurate diagnosis of liver fibrosis. Accordingly, this review delves into the latest research and advancements concerning nanomaterials in liver fibrosis diagnosis.

Comparison of Two-Dimensional Shear Wave Elastography Between Two Different Instruments for Hepatocellular Carcinoma Patients.

This study aimed to investigate and compare 2-dimensional shear wave elastography (2D-SWE) measurements and influencing factors among 2 different devices and to evaluate the ability and influencing factors of these measurements to assess liver fibrosis. From October 2022 to September 2023, 290 hepatocellular carcinoma (HCC) patients and 30 healthy volunteers were prospectively included. The 2D-SWE measurements were performed using AixPlorer V (SEmean) and APLIO i900 (CEmean). This study compared 2D-SWE measurements between instruments for evaluating the liver fibrosis stage and analyzed the potential influencing factors. The 2D-SWE measurements obtained by the 2 instruments were significantly different (P < .001), but the differences were significant only for patients with stage F4 liver fibrosis (P < .001) and not for volunteers or patients with stage F0-F3 liver fibrosis (all P > .050). Multivariate linear regression analysis revealed that the factors independently influencing the SEmean were alanine aminotransferase (ALT) (P = .034) and liver fibrosis stage (P < .001), while fibrosis stage (P = .028) was the only factor influencing the CEmean. Although 2D-SWE from the 2 different instruments was capable of detecting liver fibrosis, it yielded varying results in HCC patients. These discrepancies were predominantly observed in patients with F4 liver fibrosis but not in healthy adults or patients with F0-F3 liver fibrosis. One potential contributing factor to the differences between instruments could be ALT levels.

Cellular fibronectin-targeted fluorescent aptamer probes for early detection and staging of liver fibrosis

Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. Statement of significanceCurrently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)—a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis—are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.

Endoscopic Ultrasound Shear Wave Elastography for Fibrosis Screening in Patients with Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Pilot Study (With Video)

Background and AimsLiver fibrosis staging is challenging in patients with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Liver biopsies are invasive, whereas non-invasive tests such as vibration-controlled transient elastography (VCTE) can be inaccurate in patients with obesity. We hypothesized that endoscopic ultrasound shear wave elastography (EUS-SWE) is more accurate for liver fibrosis staging in patients with MASLD and obesity, and in this pilot study we aimed to test this hypothesis and establish optimal fibrosis stage cutoffs for EUS-SWE. MethodsThis was a multicenter, cross-sectional study from prospectively collected data. Consecutive patients who underwent EUS-SWE with subsequent liver biopsy were included. EUS-SWE was compared to Fibrosis-4 Index (FIB-4) and VCTE. Area under the receiver operator characteristic (AUROC) curve analysis was performed, and 90% sensitivity and specific cutoffs were calculated to determine optimal cutoffs. Results62 patients were included. Mean body mass index was 40.74kg/m2. EUS-SWE was superior to FIB-4 in discriminating significant fibrosis (F2; AUROC 0.87 vs 0.61, p<0.0048) and advanced fibrosis (F3; AUROC 0.93 vs 0.63 p<0.0001), but not cirrhosis (F4; AUROC 0.95 vs 0.81, p=0.099). EUS-SWE was superior to VCTE in predicting advanced fibrosis and cirrhosis (p=0.0067 and 0.0022 respectively). 90% sensitivity cutoffs for EUS-SWE were 7.50, 8.48, and 11.30 for F2-F4 respectively, and 90% specificity cutoffs were 9.82, 10.20, and 14.60 respectively. ConclusionsIn this pilot study, EUS-SWE was superior to FIB-4 and VCTE for liver fibrosis staging in patients with MASLD and obesity (Clinical trial registration number: NCT05728697).

A longitudinal 5-year study for the prediction of HCC, death and liver decompensation by ARFI elastography.

Numerous studies have evaluated elastography for the staging of liver fibrosis. Fewer studies were performed investigating the prognostic relevance using transient elastography (TE), although with promising results. This study was designed to evaluate the prognostic relevance of ARFI elastography. Patients receiving ARFI elastography in our ultrasound department between 2010 and 2012 were initially screened for an ARFI examination with a clinical follow-up of at least 5 years. The following events were recorded: liver related death, liver unrelated death, HCC, liver decompensation/ variceal bleeding. A total of 335 patients were included in the final analysis with an ARFI examination of the liver and a follow-up of 60 months. Within the observation interval the number of events with corresponding AUROCs (shown with 95% confidence interval) were: overall death (n=49, 0.76 [0.69 - 0.83]), liver related death (n=25, 0.85 [0.77 - 0.93]), liver unrelated death (n=24, 0.66 [0.55 - 0.77]), HCC (n=15, 0.80 [0.72 - 0.87]), liver related complications/variceal bleeding (n=34, 0.87 [0.82 - 0.93]). In the group of patients with ARFI values suggestive of cirrhosis (equal to or above 1.80 m/s; n=110) higher values (<2.5 m/s vs. >= 2.5 m/s) where associated with a significant decline in liver related survival (p=0.007). ARFI elastography seems to have a good diagnostic accuracy for the prediction of liver related death and decompensation. Further it seems to allow a risk stratification in patients with cirrhosis suspicious elastography values.

GLCV-NET: An automatic diagnosis system for advanced liver fibrosis using global–local cross view in B-mode ultrasound images

Background and objective: Advanced liver fibrosis is a critical stage in the evaluation of chronic liver disease (CLD), holding clinical significance in the development of treatment strategies and estimating the disease progression. Methods:This paper proposes an innovative Global–Local Cross-View Network (GLCV-Net) for the automatic diagnosis of advanced liver fibrosis from ultrasound (US) B-mode images. The proposed method consists of three main components: 1. A Segmentation-enhanced Global Hybrid Feature Extractor for segmenting the liver parenchyma and extracting global features; 2. A Heatmap-weighted Local Feature Extractor for selecting candidate regions and automatically identifying suspicious areas to construct local features; 3. A Scale-adaptive Fusion Module to balance the contributions of global and local scales in evaluating advanced liver fibrosis. Results:The predictive performance of the model was validated on an internal dataset of 1003 chronic liver disease (CLD) patients and an external dataset of 46 CLD patients, both subjected to liver fibrosis staging through pathological assessment. On the internal dataset, GLCV-Net achieved 86.9% accuracy, 85.0% recall, 85.4% precision, and 85.2% F1-score. Further validation on the external dataset confirmed its robustness, with scores of 86.1% in accuracy, 83.1% in recall, 80.8% in precision, and 81.9% in F1-score. Conclusion:These results underscore the GLCV-Net’s potential as a promising approach for non-invasively and accurately diagnosing advanced liver fibrosis in CLD patients, breaking through the limitations of traditional methods by integrating global and local information of liver fibrosis, significantly enhancing diagnostic accuracy.

AHCC inhibited hepatic stellate cells activation by regulation of cytoglobin induction via TLR2-SAPK/JNK pathway and collagen production via TLR4-NF-κβ pathway.

Cirrhosis, which represents the end stage of liver fibrosis, remains a life-threatening condition without effective treatment. Therefore, prevention of the progression of liver fibrosis through lifestyle habits such as diet and exercise is crucial. The functional food AHCC, a standardized extract of cultured Lentinula edodes mycelia produced by Amino Up Co., Ltd. (Sapporo, Japan)] has been reported to be effective in improving the pathophysiology of various liver diseases. In this study, the aim was to analyze the influence of AHCC on hepatic stellate cells, which are responsible for liver fibrosis. Eight-week-old male C57BL6/j mice were induced with liver fibrosis by intraperitoneal injection of carbon tetrachloride. Simultaneously, they were orally administered 3% AHCC to investigate its impact on the progression of liver fibrosis. Using the human hepatic stellate cell (HHSteC) line, we analyzed the influence of AHCC on the expression of molecules related to hepatic stellate cell activation. The administration of AHCC resulted in reduced expression of collagen1a, α smooth muscle actin (αSMA), and heat shock protein 47 in the liver. Furthermore, the expression of cytoglobin, a marker for quiescent hepatic stellate cells, was enhanced. In vitro study, it was confirmed that AHCC inhibited αSMA by inducing cytoglobin via upregulating the stress-activated protein kinase/Jun NH2-terminal kinase (SAPK/JNK) pathway through Toll-like receptor (TLR) 2. In addition, AHCC suppressed collagen1a production by hepatic stellate cells through TLR4-NF-κβ pathway. AHCC was suggested to suppress hepatic fibrosis by inhibition of hepatic stellate cells activation. Daily intake of AHCC from mild fibrotic stages may have the potential to prevent the progression of liver fibrosis.NEW & NOTEWORTHY AHCC, a standardized extract of cultured Lentinula edodes mycelia, suppresses liver fibrosis progression by induction of cytoglobin via the Toll-like receptor 2 (TLR2)-stress-activated protein kinase/Jun NH2-terminal kinase (SAPK/JNK) pathway and the inhibition of collagen production via the TLR4-NFκβ pathway in hepatic stellate cells. Daily oral administration of AHCC from the stage of MASLD may have the potential to prevent disease progression to MASH with fibrosis.

Lipid and carbohydrate metabolism disturbances in children with chronic hepatitis C

Aim. To study the state of lipid and carbohydrate metabolism, body composition, liver parenchyma structure in children with chronic hepatitis C (CHC).Materials and methods. 63 children with CHC examined at DNACIB in 2022–2023 (anthropometry, laboratory examination, bioimpedance analysis (BIA) of body composition, liver elastography with evaluation of steatosis).Results. Abnormalities of lipid metabolism were detected in 1/3 of children with CHC even with normal and low body mass index (BMI). Signs of insulin resistance (HOMAIR&gt;3,2) were found in 54% of children with CHC. One third of patients with insulin resistance have liver steatosis, which significantly exceeds the frequency of steatosis registration among children without insulin resistance. There was a tendency for the frequency of insulin resistance to increase in proportion to the progression of the stage of liver fibrosis. No association between hepatitis virus genotype and disorders of lipid and carbohydrate metabolism was found.Conclusion. As a result of hepatitis C virus exposure in children with CHC, the risk of insulin resistance formation increases, which may be one of the pathogenetic mechanisms of liver steatosis development, increasing the risk of severe liver fibrosis formation and unfavorable outcome of the disease.

Intestinal microbiota and metabolically associated steatotic liver disease: current understanding of the problem. Review

Cross‑interaction of microbes, microbial products, and the intestinal barrier are components of the so‑called «intestine‑liver axis», as the liver and intestines have a close two‑way relationship. In patients with metabolically associated steatotic liver disease (MASLD), significant characteristic changes in the intestinal microbiome are observed, in particular, the growth of gram‑negative bacteria, which contributes to the formation of a pro‑inflammatory status (primarily due to endotocins) and disruption of metabolic processes, while an increase in Bacteroides and Ruminococcus and a decrease in Prevotella are associated with severe stages of liver fibrosis. Intestinal microbiota modulates the pool of bile acids thereby affecting metabolic homeostasis and pro‑inflammatory processes. Dysbiosis associated with MASLD is characterized by an excess of bacteria — producers of secondary bile acids, which are one of the factors in the progression of metabolically associated steatohepatitis. In addition, dysbiosis leads to increased production of short‑chain fatty acids, which promotes gluconeogenesis, synthesis and accumulation of toxic lipids in the liver and, accordingly, the development and progression of MASLD. But liver function disorders connected with dysbiosis are associated not only with intestinal bacteria, but also with fungi and viruses. According to the results of recent studies, MASLD is associated with a significant diversity of the mycobiome and has certain differences in the progression of the disease depending on the degree of liver inflammation and the stage of fibrosis. Chronic hyperproduction of endogenous ethanol (Klebsiella pneumoniae, Escherichia, Candida, etc.) is an important factor in the pathogenesis of MASLD, as it disrupts glucose and lipid metabolism, contributing to the formation of liver steatosis and steatohepatitis. Ultrastructural and functional changes of mitochondria are recognized determinants in the pathogenesis of MASLD. Mitochondria and intestinal microbiota have a bidirectional relationship: microbiota supplies metabolites for mitochondrial metabolism and redox homeostasis, and the development of dysbiosis contributes to oxidative stress and proinflammatory status — key factors in the development of metabolically associated steatohepatitis. Mitochondria can also modulate intestinal microflora by affecting the permeability of the intestinal barrier. The data presented in the article expand our knowledge about the interaction of the liver and the intestine and inspire the development of new promising therapeutic approaches to the treatment of MASLD, which involve a synergistic effect on the intestinal microbiota, microbiome, virome, and mitochondrial function.

Impairment of health-related quality of life among people with type 2 diabetes and advanced liver fibrosis

People with type 2 diabetes mellitus (T2DM) show a high prevalence of steatotic liver disease (SLD), and especially metabolic dysfunction-associated steatotic liver disease (MASLD), with liver fibrosis. Their health-related quality of life (HRQL) is affected by multiple in part overlapping factors and aggravated by metabolic and liver-related comorbidities, including liver fibrosis stage. The aim of this study was to investigate the effect size of advanced fibrosis (AF) on the HRQL in people with T2DM. A total of 149 individuals with T2DM treated at a primary care provider within the German disease management program (DMP) were included in the final analysis. Vibration-controlled transient elastography (VCTE) was used to non-invasively detect steatosis and AF. The EQ-5D-3L questionnaire was used to assess the HRQL. Uni- and multivariable linear regression models were used to identify independent predictors of impaired HRQL. The majority was male (63.1%), and the median age was 67 years (IQR 59; 71). In the entire cohort, the prevalence of MASLD and AF was 70.7% and 19.5%, respectively. People with T2DM and AF had an overall lower HRQL in comparison to those without AF (p < 0.001). Obesity (β: − 0.247; 95% CI − 0.419, − 0.077) and AF (β: − 0.222; 95% CI − 0.383, − 0.051) remained independent predictors of a poor HRQL. In turn, T2DM-related comorbidities were not predictive of an impaired HRQL. Obesity and AF negatively affect the HRQL in patients with SLD and T2DM in primary care. Awareness of liver health and specific interventions may improve patient-reported and liver-related outcomes in people with T2DM.

Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.

To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.